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A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

2022; Nature Portfolio; Volume: 54; Issue: 9 Linguagem: Inglês

10.1038/s41588-022-01064-5

1546-1718

Danny Antaki, James P. Guevara, Adam X. Maihofer, Marieke Klein, Madhusudan Gujral, Jakob Grove, Caitlin E. Carey, Oanh Hong, María J. Arranz, Amaia Hervás, Christina Corsello, Keith K. Vaux, Alysson R. Muotri, Lilia M. Iakoucheva, Eric Courchesne, Karen Pierce, Joseph G. Gleeson, Elise Robinson, Caroline M. Nievergelt, Jonathan Sebat,

Genetics and Neurodevelopmental Disorders

The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes. Integrated analyses in a large collection of families provide insights into the combined effects of rare variants and polygenic risk on autism spectrum disorder.